This study investigates the role of Fundc1 in cardiac protection under high-altitude hypoxic conditions and elucidates its underlying molecular mechanisms. Using cardiomyocyte-specific Fundc1 knockout (Fundc1CKO ) mice, we demonstrated that Fundc1 deficiency exacerbates cardiac dysfunction under simulated high-altitude hypoxia, manifesting as impaired systolic and diastolic function. Mechanistically, we identified that Fundc1 regulates cardiac function through the mitochondrial unfolded protein response (mito-UPR) pathway. Fundc1 deficiency led to significant downregulation of multiple mito-UPR-related factors, including ATF5, Chop, and PITRM1. Further investigation revealed that Fundc1 deficiency results in increased cardiomyocyte apoptosis, calcium dysregulation, reduced cell viability, and impaired mitochondrial function, characterized by decreased ATP production, reduced membrane potential, and increased ROS production. Notably, activation of mito-UPR with oligomycin significantly ameliorated these cardiac abnormalities in Fundc1-deficient mice. We identified ATF5 as a key downstream effector of Fundc1, as ATF5 overexpression effectively reversed cardiac dysfunction and restored mito-UPR-related gene expression in Fundc1-deficient hearts. Additionally, we discovered that Fundc1-mediated cardioprotection involves regulation of mitophagy, where its activation improved cardiac function and mitochondrial homeostasis in Fundc1-deficient mice. Our findings reveal a novel Fundc1-ATF5-mito-UPR axis in cardioprotection against high-altitude hypoxia and highlight the crucial role of mitophagy in this protective mechanism, providing new insights into potential therapeutic strategies for high-altitude heart disease.
Keywords: ATF5; FUNDC1; mito-UPR; mitochondria..
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